Network pharmacology and experimental analysis reveal Ethyl caffeate delays osimertinib resistance in lung cancer by suppression of MET.

BACKGROUND: Fei Yanning Formula (FYN) is extensively applied in clinical lung cancer treatment. However, the specific active constituents and targets of its therapeutic effects remain unclear. OBJECTIVE: The study aims to explore the active constituents and mechanism of FYN in delaying osimertinib resistance by network pharmacology analysis and experimental verification. METHODS: We collected the chemical constituents of the FYN based on the TCMSP database and relevant literature sources. Osimertinib resistance-related targets were acquired from the GeneCards database. We systematically construct the PPI network and KEGG analysis to explore hub targets and key pathways. The main active components of FYN were identified by molecular docking. Subsequently, we conducted in vitro experiments to verify its effect on osimertinib-resistant cells in lung cancer. RESULTS: The PPI network and KEGG pathways analysis revealed six key targets linked to PI3K-AKT signaling pathways (ERBB2, EGFR, MET, HSP90AA1, MCL1, and IGF1R). RT-qPCR and immunohistochemical analyses demonstrated that FYN could suppress the expression of ERBB2, MET and HSP90AA1. Molecular docking indicated that Ethyl caffeate, the primary component in FYN, had a stronger binding ability with MET. Experiments illustrated that Ethyl caffeate inhibited the migration and proliferation of osimertinib-resistant cells, promoted apoptosis, and suppressed the expression level of MET. CONCLUSION: FYN might delay osimertinib resistance by downregulating the expression of MET, which can be attributed to its active ingredient, Ethyl caffeate.